PROJECT SUMMARY The epigenome controls cancer identity and behavior. Discovering epigenetic changes that occur during cancer initiation, progression, and development of therapeutic resistance will reveal key cancer drivers, and lead to development of robust targeted therapies. My current and future research goals aim to delineate the cancer epigenome in two highly aggressive cancers, triple-negative breast cancer (TNBC) and high grade serous ovarian carcinoma (HGSOC), and elucidate how the epigenome changes with disease progression. I will then use this information to identify targetable mediators of the aggressive phenotypes of these diseases. My dissertation research focuses on BET inhibitors (BETi), drugs that selectively target the BET protein family of epigenetic readers. Although BETi are effective in many cancer models, their mechanism of action is not well understood, and little is known regarding their efficacy in TNBC and HGSOC. My studies show that BETi inhibit growth of diverse TNBC cell lines in vitro and in vivo and are the first to establish mitotic catastrophe as the underlying mechanism of BETi inhibition of TNBC. During the F99 portion of this proposal, I will extend my work in TNBC to assess the activity of BETi in HGSOC, a genetically similar disease. HGSOC is the most aggressive subtype of ovarian cancer, frequently develops resistance to platinum-containing agents, and has experienced few advances in treatment over the last two decades. My proposed studies thus center around four main goals: 1) determine the activity of BETi in models that accurately represent HGSOC, 2) assess whether BETi synergize with cisplatin, 3) use a comprehensive analysis to identify the cisplatin resistance-associated transcriptome, and 4) determine if BETi revert the cisplatin resistant transcriptome. While my predoctoral research will focus on the use of BETi and how they modulate the transcriptome, I will use my postdoc to enhance my understanding of the epigenetic landscape that regulates HGSOC phenotypes. My research will build upon my initial studies of BETi activity in HGSOC to ultimately define the epigenetic drivers of ovarian cancer growth, metastatic progression, and therapeutic resistance. Specifically, I will identify the super-enhancers that define ovarian cancer and how changes to the enhancer landscape initiate metastasis and therapeutic resistance. I will also perform additional experiments examining chromatin structure and regulation. Data from these studies will be merged with the super-enhancer landscape and other available HGSOC epigenomic information to identify the regulatory mechanisms of HGSOC and determine how shifts in the epigenome influence aggressive phenotypes. These studies will also reveal novel potential targets that impact HGSOC development, progression, and drug resistance. Together, my predoctoral and postdoctoral research will provide me with incomparable expertise in the epigenetic control of transcription in breast and ovarian cancers and how epigenetic modifications induce metastasis and drug resistance. I will use these skills to launch my independent research career that focuses on identifying new therapeutic strategies to treat these aggressive cancers.